There is a lot of mythology about prostate cancer. One of the prevalent myths is that a Gleason score 6 (GS6) found with a biopsy, or even confirmed over many biopsies, never progresses. How did the myth get started and what is the truth, as we know it so far?
Metastases never come directly from GS6 in the prostate (true)
This is true. Donin et al.
at NYU Langone looked at the records of 857 patients diagnosed as GS6 after a prostatectomy. 16 of them were found to have a significant recurrence and were treated with salvage radiation to the prostate bed. All but 2 of the treated patients had no further recurrence, indicating that there were no distant metastases. The remaining two were found to have actually had GS7 when their removed prostates were re-examined.
Ross et al.
looked at records from Johns Hopkins, UCSF, Baylor and Henry Ford and found 22 cases (out of 14,123 examined) where pelvic lymph node metastases were found during prostatectomies of GS6 patients. 19 of those were re-reviewed, and all were found to have a higher Gleason score than the initial pathology assessment. Lymph node metastases were never
associated with a GS6. Similarly, Liu et al.
searched the 2004-2010 SEER database to find 21,960 GS6 patients who had pelvic lymph node dissection along with their prostatectomy. Only 0.48% were found to have lymph node metastases. Unfortunately, their prostate specimens were not available for re-review. Wenger et al.
looked at the 2004-2011 SEER database, the 2004-2013 National Cancer Database, and 2004-2013 patient records at the University of Chicago; lymph node metastases were found in 0.2%, 0.18%, and 0%, respectively, among the GS6, post-prostatectomy records. Of the 24 patients at U. of Chicago who had a recurrence, all but 3 were local. The 3 non-local recurrences were all found to have been GS7 on pathological re-review.
In a Dutch study of 449 GS6 post-prostatectomy patients treated from 1985-2013 with over 8 years of median follow-up, Kweldam et al.
found that there were no lymph node metastases, no distant metastases, and no prostate-cancer related deaths.
Not only does true GS6 never metastasize, it rarely eats into surrounding tissue. Anderson et al.
looked at post-prostatectomy records of 2,502 GS6 patients from the University of Chicago and Northwestern treated from 2003-2014. Only 7 of them were found to exhibit extraprostatic extension (stage pT3a), and it was only focal in every case. There were no cases of seminal vesicle invasion (stage pT3b) or invasion of organs adjacent to the prostate (stage pT4). Hassan et al.
at Johns Hopkins looked at post-prostatectomy records of 3,288 GS6 patients treated from 2005-2016. 3.9% exhibited focal
extraprostatic extension, 2.4% exhibited significant (non-focal) extraprostatic extension, and there was only one case of seminal vesicle invasion.
A GS6 at biopsy may not be a true GS6 (true)
In a study at Johns Hopkins among low-risk patients who decided to have a prostatectomy, Epstein et al.
reported that 36% were upgraded from a GS6 to a higher grade. Lotan et al.
report a similar amount of upgrading (40%) even if a 32-core saturation biopsy was used. Multiparametric MRI targeting can find GS7 or greater tumors if they are large enough (> 2 cc), but Bratan et al.
reported that the GS7 detection rate was only 63% for tumors < 0.5 cc, and 82-88% for tumors 0.5-2.0 cc. An NIH study
used mpMRI imaging on patients who immediately afterwards had a prostatectomy. The mpMRI was evaluated by their expert readers who looked for cancers larger than 5 mm and with grades of at least GS 3+4. The mpMRI missed 16% of clinically important tumors.
Multiple biopsies over the years can increase the odds of finding any cancer that is GS7. Even if a single mpMRI-targeted biopsy misses 37% of small GS7 tumors, the odds that two such biopsies will miss it is 37% x 37% = 14%. Three biopsies drop the odds to 1 in 20, and the odds of missing it on 4 biopsies is 1 in 53. Multiple biopsies are used in most active surveillance protocols, and their frequency can be slowed if there is no evident progression. Some of the increased detection with multiple biopsies will be due to better detection of what was always there, some will be due to grade progression (see below), and it really doesn't matter which is which.
A GS6 may progress into something else that can metastasize (true)
GS6 is a relatively indolent type of prostate cancer. Most of it never progresses to higher grades, but some of it will, given enough time. In the longest-running active surveillance study in North America, Klotz reports
that 55% of low-risk patients have been able to avoid treatment due to grade progression for 20 years. Conversely, 45% did have grade progression. Only 25% had progressed in the first 5 years, 37% by 10 years, and 45% by 15 years. After that, cases of progression came to a halt. An active surveillance model at Johns Hopkins
, which had strict annual biopsies, attempted to separate the misclassifications from the true grade progression. They estimated that the true grade progression rate in the first 10 years was 12%-24%. A similar model
estimated the rate of total grade progression (true progression plus correction of prior misclassification) at about 4% per year during the first ten years, and they determined that the time for those GS6s that progressed to a GS7 took an average of 14 months.
Watkins et al.
reported that GS6 patients had a low risk of recurrence after prostatectomy unless they had positive surgical margins. 8-year freedom from biochemical recurrence was 95% with no positive margins, but only 74% if there were any positive margins. GS6 left in the body can still proliferate and progress.
A large retrospective study at Harvard
reported that among the 410 deaths from prostate cancer in an advanced prostate cancer cohort, 42 (10%) were originally biopsy-diagnosed as GS 6. GS 6 doesn't often turn into something lethal, but it can.
Further evidence of grade progression comes from a cohort of 1041 Swedish patients
who had a PSA test but were not biopsied at that time. Gleason score was found to be correlated with the "lead time" between the date of the elevated PSA (3.0-10.0) and the biopsy when symptoms occurred. The diagnosis of higher grade cancers rose steadily throughout the up to 30 years of lead time in the study. Inversely, the diagnosis of low grade cancers dropped steadily with lead time. The low grade cancers converted to high grade cancers over time.
(update July 2020) Salami et al.
found that certain molecular "fingerprints" existed in the cancers that were GS6 and remained in their cancers after the patients progressed to higher grades.
There are some risk factors that can help distinguish the GS6s that will progress from the ones that won't (partly true)
There are several risk factors associated with higher grade cancers (e.g., PSA, PSA density, age, and African-American); however, none of them have a cutpoint that discriminates between those who will progress from GS6 and those who won't. Ellis et al.
at Johns Hopkins showed that the number of positive biopsy cores (≤6 or >6) did predict grade progression at prostatectomy to some extent:
- 23% were upgraded if there were ≤6 positive cores
- 34% were upgraded if there were >6 positive cores
- But it had little effect on the recurrence-free survival following prostatectomy .
Perineural invasion (PNI) noticed in the biopsy may be prognostic for progression on GS6, especially when both PNI and a high percentage of cancer in cores are found (see this link
). Johns Hopkins has tables
from which a patient with PNI may estimate his risk that the cancer is not confined to the prostate capsule based on GS, PSA, and the highest % cancer in a biopsy core.
Genetic risk can sometimes identify patients who are at higher risk for grade progression than their low risk NCCN designation would indicate. Prolaris and Oncotype Dx will usually indicate genetic risk in line with NCCN risk group, but sometimes they may find higher risk than expected. Recently, Decipher has begun to offer genomic risk scores based on biopsy samples. There is some evidence that there may be wide genetic diversity of the multiple tumors within a man's prostate. Just as a single biopsy may miss a high grade cancer, the biopsy cores sent for genetic analysis may not include the one or ones with higher genetic risk. These tests are expensive ($3,000-$4,000) and may not be covered by insurance (always get preauthorization!).
PSA inconsistently goes up with grade, and some high grade disease puts out low levels of PSA. Compared to total PSA, the PSA-derived biomarkers (e.g., Free PSA, PHI, 4Kscore, IsoPSA) have higher detection rates of high grade prostate cancer, as do PCA3, TMPRSS2:ERG fusion, and Select MDx.
How does GS6 progress to higher grades? What can we do about it?
There is very little certainty about the changes that occur at the molecular level when GS6 cancer progresses, and what drives those changes. Sowalsky et al.
found that Gleason pattern 4 glands that were intermixed or adjacent to Gleason pattern 3 glands shared characteristic genetic markers that indicated they had a common origin. Whether the pattern 4 cells were cloned directly from pattern 3 cells or arose from a common precursor cell is not clear. The authors suggest that a genetic aberration called "PTEN loss" may distinguish pattern 3 cells that might progress from the kind that might not progress.
VanderWeele et al.
did a genetic analysis of 4 patients who had both GS6 and GS8 tumors in the same prostate. Two of the men also had lymph node metastases that were analyzed. They found that the GS6 and GS8 cells shared 9% of the characteristic genes they looked for. That suggested that GS6 did not directly morph into GS8, but arose from an early common ancestor long before. On the other hand, the GS8 shared 81% of those characteristic genes with the lymph node metastases, indicating recent progression.
Haffner et al.
did a genetic analysis of a metastasis from a patient who recently died of prostate cancer. They also analyzed tissue samples taken from the man's earlier prostatectomy and lymph node dissection. They found that the lethal metastasis was much more closely related to a small bit of pattern 3 cancer in the prostate rather than to the pattern 4 cancer in the "index lesion" (the largest, highest grade tumor in the prostate) or to the lymph node metastasis. The lymph node metastasis, however, was not clonally related to the pattern 3 cancer, and seems to have arisen from a different source. The authors suggest that PTEN loss and loss of another tumor-suppressor gene called TP53 may distinguish the potentially lethal pattern 3 cancer from the innocuous kind.
Palapattu et al.
used MRI/Ultrasound fusion biopsy to take sequential cores from exactly the same place on study entry and one year later from 31 low-risk men on active surveillance. 35% progressed to a higher grade (pattern 4 or 5) in the same site in that year. It was from the same tumor because it had characteristic gene expression in almost every case. They found several suspicious genetic mutations. Mutations in the genes SPOP and IDH1 were common to both the low grade and high grade cells in one patient each, suggesting they may be responsible for progression. In one patient, a TP53 mutation was found in the later high grade core, but not the earlier low grade core, suggesting it is the result of something else that caused progression. Mutations in SPOP and BRCA2 were found in only the later cores in two patients who did not yet progress, perhaps suggesting increased potential for progression. As opposed to the studies that suggest a common progenitor cell for low and high grade cancer, this study suggests that genetic abnormalities and accumulating genetic breakdown are the sources of grade progression.
These studies are beginning to offer clues as to why GS6 sometimes progresses. There are biomarkers like Ki67, p53, and VPAC that may predict progression. Histological analysis may detect PTEN loss and TP53 loss, as well as mutations in SPOP, IDH1, and BRCA2 in tumor genes. While we currently lack widely available means to predict progression, active surveillance with periodic biopsies remains our best tool for finding progression while it is still curable.
Unfortunately, there are no medicines that can prevent grade progression from occurring, or reverse it after it does occur. Perhaps someday, CRISPR or zinc fingers will be used, but that is many years away.